Patients with painful bladder syndromes such as interstitial cystitis (IC) characterized by urinary frequency, urgency, and bladder pain often exhibit urethral or pelvic pain. It is also documented that peripheral nerve injury in the pelvis may contribute to the emergence of bladder and/or pelvic pain because surgical manipulation of visceral organs is known to be a risk factor for the IC, and also often leads to aggravation of existing symptoms or onset of new symptoms in patients with pelvic pain. The urethra, urethral sphincter muscles and the pelvic floor are innervated by a subset of visceral (pelvic and hypogastric) and somatic (pudendal) afferent fibers which are a more diverse population (C, Asigma and Abeta-fibers; possibly Aalpha-fibers) than those innervating the urinary bladder (C and Asigma-fibers). However, little is known about their functional characteristics and changes under chronic pathological conditions including tissue inflammation or nerve injury that may result in chronic urethral or pelvic pain. Thus, in this research project, electrophysiologic, pharmacologic, molecular and neurochemical techniques will be used to examine the characteristics of urethral afferent neurons and somatic afferent neurons in the pudendal nerve. We are particularly interested in characterizing membrane properties of these afferent neurons, and also in identifying how the chemical mediators or pathology alter ion channel and receptor properties, leading to neuronal hyperexcitability. Several hypotheses will be tested: (1) Multiple subtypes of afferent neurons can be identified based on their functional and morphological properties including tetrodotoxin-resistant Na+ channels, slow-inactivating transient K+ channels, vanilloid receptors (VR1) sensitive to capsaicin, and immunoreactivity against specific cellular markers such as neurofilament or isolectin-B4, (2) Chronic inflammation of the urethra/pelvic floor or direct injury to the pudendal nerve alters the expression of ion channels or neurotransmitter mechanisms in afferent neurons, resulting in hyperexcitability of these neurons. These changes might be different from those that we have been recently identified in bladder afferent neurons, (3) Functional changes in urethral afferent neurons or pudendal afferent neurons under chronic pathological conditions can induce bladder and/or urethral hyperactivities by reorganizing viscerosomatic reflex activities. The long-term objectives of the research program are to understand the mechanisms by which irritating or nerve-injuring stimuli in pelvic organs induce phenotypic changes in their afferent pathways and thereby trigger chronic pain in the pelvis. If a specific relation is found between different pathology and alteration in ion channel or receptor properties/expression, it is possible to identify new molecular target of drug therapy for chronic bladder and/or pelvic pain associated with painful bladder syndromes.